Conformational restriction of Tyr and Phe side chains in opioid peptides: Information about preferred and bioactive side-chain topology

✍ Scribed by Dirk Tourwé; Kris Verschueren; Anne Frycia; Peg Davis; Frank Porreca; Victor J. Hruby; Geza Toth; Hendrika Jaspers; Patricia Verheyden; Georges Van Binst

• Publisher: Wiley (John Wiley & Sons)
• Year: 1996
• Tongue: English
• Weight: 789 KB
• Volume: 38
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/(sici)1097-0282(199601)38:1<1::aid-bip1>3.0.co;2-#

✦ Synopsis

The side chain of T w and Phe was,fixed into the gauche (-) or gauche (+) conjormation by using the Tic or Htc structura, and into the trans conformation by using an aminobenzazepine-t)~e (Aha) structure. When incorporated into dermorphin or deltorphin II, the Tic and Htc analogues all showed a large decrease in both i.i and6 afinities and activities. Fixation OfPhe" in the trans rotamer rmtlted in a large increase in 6 afinity in the dermorphin analogue, whereas in the [Aba"-Gly4] deltorphin 11 analogue, good 6 afinity is maintained despite the removal of the Glu side chain. Whereas several authors propose a gauche (-) preferred confirmation for the Phe" side chain, these results suggest a trans conformution at the 6 receptor. The use of these conjormationally constrained re.sidues,fi,r c u d mating the prekrred solution confornmtion in theflexible N-terminal tripeptide Tyr-D-Ala-Phe is illustrated. The ' H-nmr parameters-chemical shiji, temperature dependence, and nuclear Overhauser effects to the u-Ala2 methyl protons in the different analogues-provide direct evidence to confirm the proposed sandwich conformation in the native peptide.7.